An overactive bladder is a clinical condition showing urinary urgency regardless of incontinence, which is usually accompanied by urinary frequency and nocturia (Non-Patent Document 1). At present, for a treatment thereof, an anticholinergic agent is mainly used for a treatment thereof, and constant treatment results are given. However, it has been reported that the use thereof is difficult with patients with prostatic hypertrophy or elderly patients because it is known to cause side-effects such as dry mouth, constipation and blurred vision, as well as a risk of urinary retention. In addition, there are patients who show no improvement with the anticholinergic-treatment. From the above, there is great expectation of a drug with a new mechanism of action for overactive bladder.
A nerve growth factor (NGF) is one of the humoral factors named generically as a neurotrophic factor, which plays an important role in the development, differentiation and functional maintenance of neurons in the living body. As a receptor of NGF, a high-affinity trkA receptor (tyrosine kinase receptor) and a low-affinity p75 receptor have been known. It has been reported that p75 binds to all neurotrophic factors, and is involved in apoptosis in the process of neuron development, but the role has not yet been fully understood. It has been known that NGF and trkA receptor-knockout mice show the similar phenotype (Non-Patent Document 1), and it is believed that the physiological action of NGF is exhibited mainly through the trkA receptor.
It has been known that the NGF level in bladder is increased in a patient with overactive bladder or interstitial cystitis (Non-Patent Document 2), and there have been reports that an intravesical instillation of NGF reduces the bladder capacity of a rat and that the inhibition of NGF improves urination function in the urinary frequency-model rat (Non-Patent Document 3). In addition, it has been reported that the inhibition of NGF improved urinary frequency or urinary incontinence in a patient with interstitial cystitis (Non-Patent Document 4), and it is thus believed that a trkA receptor inhibitor is useful as a therapeutic agent for lower urinary tract diseases such as overactive bladder, interstitial cystitis, prostatitis, and the like.
Moreover, a trkA receptor inhibitor has different mechanisms of action, and thus the side effects specific to the anticholinergic agent are expected to be avoided as well as an effect on patients who showed no improvement with the anticholinergic treatment is expected. In addition, this agent is expected to have potent effects of improving the subjective symptoms by acting on sensory nerves. Furthermore, this agent has been reported to exhibit an effect of improving the clinical condition without lowering urinary pressure in the urinary frequency-model rat (Non-Patent Document 5), and thus is expected to be administered safely to a patient with prostatic hypertrophy or an elderly patient.
It has been known that when NGF is administered to a human or a rat, pain is induced, and that pain sensation in the trkA receptor-knockout mice is lost. Consequently, NGF is believed to be strongly related to expression of pain. An NGF inhibition shows efficacy in model animals with neuropathic pain or inflammatory pain, such as a model with pain induced by damage to the ischiadic nerves (Non-Patent Document 6) and a model with pain induced by damage to the knee joint (Non-Patent Document 7), and a trkA receptor inhibitor is believed to be useful as a therapeutic agent for various pains such as lower urinary tract disease accompanied by lower urinary tract pain, osteoarthritis, or the like.
As the compound mentioned above, there have been known an indolocarbazole derivative (Non-Patent Document 8), a pyrrolocarbazole derivative (Patent Document 1), a pyrazolone derivative (Patent Document 2), an oxyindole derivative (Patent Documents 3 and 4), an azaoxyindole derivative (Patent Document 5), a pyrazoryl condensed ring compound (Patent Document 6), a pyrazole derivative (Patent Documents 7 and 8), a tricyclic derivative (Patent Document 9), ALE-0540 (Patent Document 10), a benzo[de]isoquinoline derivative (Patent Document 11), a benzo[lmn]phenanthroline derivative (Patent Document 12), and a pyrrolotriazine derivative (Patent Document 13).    Patent Document 1: Pamphlet of International Publication WO01/14380    Patent Document 2: Pamphlet of International Publication WO01/32653    Patent Document 3: Pamphlet of International Publication WO02/20479    Patent Document 4: Pamphlet of International Publication WO02/20513    Patent Document 5: Pamphlet of International Publication WO03/027111    Patent Document 6: JP-A-2003-231687    Patent Document 7: Pamphlet of International Publication WO2005/049033    Patent Document 8: Pamphlet of International Publication WO2005/103010    Patent Document 9: Pamphlet of International Publication WO2005/076695    Patent Document 10: Pamphlet of International Publication WO01/78698    Patent Document 11: Pamphlet of International Publication WO2007/030939    Patent Document 12: Pamphlet of International Publication WO2007/030934    Patent Document 13: Pamphlet of International Publication WO2007/061882    Non-Patent Document 1: ‘Reviews in the Neurosciences’, (UK), 1997, vol 8, pp. 13 to 27    Non-Patent Document 2: ‘British Journal of Urology’, (UK), 1997, vol 79, pp. 572 to 7    Non-Patent Document 3: ‘Neuroscience’, (USA), 1997, vol 78, 2th Issue, pp. 449 to 59    Non-Patent Document 4: ‘General Outline preliminarily described for the 99th American Urology Association’, San Francisco, 2004, #363    Non-Patent Document 5: ‘The Journal of Urology’, (USA), 2005, vol 173, pp. 1016 to 21    Non-Patent Document 6: ‘Pain’, (USA), 1999, vol 81, pp. 245 to 55    Non-Patent Document 7: ‘Pain’, (USA), 2005, vol 116, pp. 8 to 16    Non-Patent Document 8: ‘Cancer Research’, 1999, vol 59, pp. 2395 to 2401